# Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $408,318

## Abstract

Accumulating evidence implicates inflammation and immune responses in the pathophysiology of
stroke. Immunomodulation has therefore emerged as a promising therapy for stroke. Regulatory
lymphocytes, including CD4+CD25+ regulatory T cells (CD4+ Treg) and IL-10+ regulatory B cells (Bregs) are
established modulators of immune responses in the injured brain. We recently discovered that another
specialized T cell subpopulation—the CD8+CD122+CD49dhigh regulatory T cell—is among the first to enter
the ischemic brain, even preceding the infiltration of CD4+ Tregs and Bregs. The primary function of CD8+
Tregs is to modulate the activities of other immune cells, especially effector T lymphocytes, and to maintain
immune homeostasis. We found that selective depletion of circulating CD8+ Tregs exacerbated brain injury
and functional outcomes at 3 and 7 days after stroke, and this could be reversed by the reconstitution of
CD8+ Tregs. These exciting results suggest that CD8+ Tregs are natural defenders against ischemic brain
injury. Further pilot studies discovered that: 1) CD8+ Treg-afforded early protection relies on their infiltration
into the ischemic brain, as CD8+ Tregs lacking the “brain targeting signal” CXCR3 do not infiltrate into the
ischemic brain and lose their capacity to reduce brain infarction in CD8+ Treg-depleted mice. 2) The
infiltrated CD8+ Tregs undergo genomic reprogramming upon brain infiltration and transcriptional
upregulation of a group of genes that possess inflammation-resolving and/or neurorestorative functions,
including the leukemia inhibitory factor (LIF) receptor and epidermal growth factor-like transforming growth
factor (ETGF). 3) Post-stroke adoptive transfer of CD8+ Tregs significantly reduces brain infarct, enhances
white matter integrity, and improves neurological functions up to 14d after tMCAO. 4) Adoptive transfer of
ETGF-deficient CD8+ Treg fails to protect against tMCAO. The current proposal will further explore the effects
of CD8+ Tregs in ischemic stroke and develop CD8+ Treg adoptive transfer as an immune therapeutic therapy
for stroke. The novel central hypothesis to be tested is that brain infiltration of CD8+ Tregs promotes
long-term neurological recovery after stroke through LIF/LIFR/ETGF-mediated neuroprotection, resolution of
neuroinflammation, and neurorestorative mechanisms. Three specific aims are proposed. Aim 1. Establish
post-stroke adoptive transfer of CD8+ Tregs as a clinically relevant treatment against acute ischemic brain
infarct. Aim 2. Test the hypothesis that post-stroke adoptive transfer of CD8+ Tregs promotes long-term
neurological recovery and neurorestoration after ischemic stroke. Aim 3. Test the hypothesis that
LIF/LIFR-mediated release of ETGF is essential for CD8+ Treg-afforded neuroprotection and
neurorestoration. This study will be the first to rigorously investigate the role of CD8+ Tregs in ischemic brain
injury. The results will improve our understanding of stroke immunomodulation ...

## Key facts

- **NIH application ID:** 10261320
- **Project number:** 5R01NS105430-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jun Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $408,318
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10261320

## Citation

> US National Institutes of Health, RePORTER application 10261320, Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery (5R01NS105430-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10261320. Licensed CC0.

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